CN106692175A - Application of miR-665-3p inhibitor to preparation of medicine for preventing and treating ischemia-reperfusion injuries - Google Patents
Application of miR-665-3p inhibitor to preparation of medicine for preventing and treating ischemia-reperfusion injuries Download PDFInfo
- Publication number
- CN106692175A CN106692175A CN201611217632.9A CN201611217632A CN106692175A CN 106692175 A CN106692175 A CN 106692175A CN 201611217632 A CN201611217632 A CN 201611217632A CN 106692175 A CN106692175 A CN 106692175A
- Authority
- CN
- China
- Prior art keywords
- mir
- inhibitor
- intestinal
- preventing
- application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses application of a miR-665-3p inhibitor to preparation of a medicine for preventing and treating ischemia-reperfusion injuries. The application proves that the miR-665-3p inhibitor can be used for remarkably improving the tolerance of intestinal cells on the ischemia-reperfusion injuries and alleviating the severity degree of the intestinal ischemia-reperfusion injuries; the miR-665-3p inhibitor is used for effectively alleviating phenomena of scaling and lodging of intestinal villi of mice, expansion and exposure of blood capillaries and the like; the miR-665-3p inhibitor can be used for remarkably inhibiting excessive releasing of intestinal injury marker intestinal fatty acid binding protein (I-FABP) and inflammatory cell factors including TNF-alpha and IL-6; and meanwhile, when the miR-665-3p inhibitor is used, the survival rate of mice subjected to mouse II/R injuries for 24h is remarkably higher than that of a control group.
Description
Technical field
Lack in preparation preventing and treating the present invention relates to the new application of miR-665-3p mortifiers, especially miR-665-3p mortifiers
Application in blood reperfusion injury medicine.
Background technology
Ischemical reperfusion injury refers to cause cell that pathology change occurs after tissue ischemia anoxic reaches certain hour and degree
Change, after blood supply is recovered, not only the tissue of damage occurs the pathological phenomenon for further aggravating without function is recovered, on the contrary.
Numerous documents and materials show that ischemical reperfusion injury may be relevant with following a number of factors：1. the generation of oxygen radical；2. calcium
Overload；3. neutrophil leucocyte（PMN）Activation；4. excessive Apoptosis；5. large amount of cell factor and inflammatory mediator are released
Put.In a word, ischemical reperfusion injury is influenced each other by various mechanism, the result of comprehensive function.
Autophagy is the degradation pathway that a kind of lysosome being widely present in eucaryote is relied on, and is cell survival, growth
With the indispensable mechanism of intracellular homeostasis.Autophagy can be by aging of degrading, damaging cells device and long half-lift albumen
Cell Homeostasis are maintained, stress be under environment, appropriateness activation autophagy then can be by regenerating metabolic precursor thereof and removing subcellular fragments
Cell integrity is maintained, mitigates cellular oxidation stress damage, Apoptosis, inflammatory factor release is reduced, outside enhancing cell resistance
The ability that boundary stimulates.
Microrna（microRNA, miRNA）RNA polymerase transcription in a class eucaryote, with cap sequence
With the non-coding type RNA of polyadenylic acid tail, general length is 22-24 nucleotides.Ripe miRNA can and particular target
3 ' UTR regions of gene mRNA are complementary to be combined, so that induce silencing complex degraded target mRNA or block its translation process, most
The expression of regulation and control target gene eventually.Multiple pathophysiological processes in miRNA controllable biology growing growth courses：Cell increases
Grow, oxidative stress, Apoptosis etc..Although recent studies have shown that miRNA plays essence in multiple different phases of cell autophagy
Thin regulating and controlling effect, but, also do not preparing prevention or treatment Ischemia Reperfusion on miR-665-3p mortifiers so far
The relevant report applied in note damage medicine.
The content of the invention
The present invention is to be found that miR-665-3p mortifiers have the effect of prevention and treatment ischemical reperfusion injury, so that
Application of the miR-665-3p mortifiers in preventing and treating ischemical reperfusion injury medicine is prepared is invented.
Technical solution of the invention is：A kind of miR-665-3p mortifiers are preparing preventing and treating ischemical reperfusion injury medicine
Application in thing.
Application of the miR-665-3p mortifiers in preventing and treating Intestinal ischemia reperfusion injury medicine is prepared.
The DNA sequence dna of the miR-665-3p mortifiers such as SEQ ID NO:1 or SEQ ID NO:Shown in 3.
It is resistance to for ischemical reperfusion injury intestinal cell to be remarkably improved present invention demonstrates miR-665-3p mortifiers
By property, mitigate the order of severity of Intestinal ischemia reperfusion injury, show as effectively alleviating the lodging of morbidity mouse small intestine fine hair
And come off, the expansion of capillary and the phenomenon such as exposed；MiR-665-3p mortifiers can significantly inhibit intestinal tract injury label intestines
Type fatty acid binding protein（I-FABP）And the excessive release of inflammatory cytokine TNF-α and IL-6, while miR-665-3p presses down
24h survival rates are significantly higher than control group after thing processed is damaged for mouse II/R, can be applied to prepare preventing and treating ischemical reperfusion injury
Medicine.
Brief description of the drawings
Fig. 1 is LNA-miR-665-3p treatment rear intestinal histopathology figures.
Fig. 2 is the change of serum relevant cell factor after LNA-miR-665-3p treatments.
Fig. 3 is the influence of LC3 protein expressions after LNA-miR-665-3p is damaged to mouse II/R.
Fig. 4 is influences of the LNA-miR-665-3p to small intestine cells original position apoptosis after mouse II/R.
Fig. 5 is the influence that LNA-miR-665-3p treatments damage 24h survival rates for mouse II/R.
Fig. 6 is the influence that Antagomir-665-3p treatment damages survival rate for Caco-2 cells H/R.
Fig. 7 is the influence of autophagy stream after Antagomir-665-3p treatment is damaged for Caco-2 cells H/R.
Fig. 8 is the influence of apoptosis after Antagomir-665-3p treatment is damaged for Caco-2 cells H/R.
Fig. 9 is the influence that inflammatory factor discharges after Antagomir-665-3p treatment is damaged for Caco-2 cells H/R.
Specific embodiment
Test method used in following embodiments is conventional method unless otherwise specified.
Material, reagent used in following embodiments etc., unless otherwise specified, commercially obtain.
The miR-665-3p mortifiers used in this experiment are broadly divided into two kinds：
1. the artificial sequence synthesized oligonucleotide modified based on novel lock nucleic acid（LNA）, it is mainly used in zoopery.
LNA-665-3p sequences such as SEQ ID NO:Shown in 1；
LNA-NC control sequences such as SEQ ID NO:Shown in 2；
LNA-miR-665-3p sequences and LNA-NC control sequences entrust Exiqon biotech firms of Denmark to synthesize.
2. by special marking and the efficient blocking agents of miRNA of chemical modification（Antagomir）, it is mainly used in cell reality
Test.
Antagomir-665-3p sequences such as SEQ ID NO:Shown in 3；
Antagomir-NC control sequences such as SEQ ID NO:Shown in 4：
Antagomir-665-3p sequences and Antagomir-NC control sequences entrust Shanghai JiMa pharmacy Technology Co., Ltd
Synthesis.
Experimental example 1.LNA-miR-665-3p can effectively treat injury of small intestine caused by ischemia-reperfusion
The C57BL/6J mouse of 24 health are divided into 4 groups：
A. Normal group：Sham-operation group；
B. normal administration group：Sham-operation+LNA-miR-665-3p（2 mg/kg）；
C. model group：Intestinal ischemia/reperfusion group（II/R groups）；
D. model administration group：II/R+LNA-miR-665-3p（2 mg/kg）.
This experiment builds small intestine I/R animal models using Megision methods, and brief step is as follows：Mouse general anaesthesia, treats
After anesthesia comes into force, dorsal position is fixed on small animal surgical platform, Median incision on upper abdomen is taken after preserved skin and successively enters abdomen, softly separates intestines
Artery on mesentery（SMA）, pressed from both sides using minisize non-invasive blood vessel clip in SMA roots and closed.It is small now it was observed that the beating of SMA distal ends disappears
Intestinal wall is changed into pale asphyxia by pink rapid, confirms that SMA ischemics are successfully constructed, and small intestine also received into abdominal cavity, successively closes abdomen.Wait to lack
The blood time reaches 45 min, continues to use former otch and enters abdomen, removes minisize non-invasive blood vessel clip, proceeds by Reperfu- sion.The h of Reperfu- sion 4 is tied
Shu Hou, row abdominal aortic blood puts to death animal.Normal group mouse is parallel to be anaesthetized, and opens the step such as abdomen and SMA separation, but
SMA folders are not carried out to close.Each group mouse when Reperfu- sion starts the ml/kg of hind leg hypodermic injection physiological saline 12 with fluid infusion.
LNA-miR-665-3p is dissolved using aseptic TE buffer, 10 mg/ml storage liquid is configured to.Preoperative 12 h is used
Sterile saline prepares parenteral solution, and normal administration group and model administration group are administered by caudal vein（2 mg/kg）, it is administered negative
Lotus is 0.1 ml.
1.1 small intestine's pathology
Taking small intestine carries out HE dyeing, in 400 times of light Microscopic observations.As shown in figure 1, Normal group（A）And normal administration
Group（B）：Small intestinal mucosa fine hair marshalling, form is complete, and SES is without expansion；Model group（C）：Intestinal villi arrangement is disorderly
Disorderly, the visible a large amount of fractures in top and come off, SES is broadening, capillary extravasated blood；Model administration group（D）：Intestinal villi
The degree that comes off mitigates, and epithelium is slightly separated with lamina propria.Test result indicate that, LNA-miR-665-3p can significantly mitigate ischemic again
The damage of mouse small intestine tissue caused by perfusion.
The change of 1.2 serum cytokines
Using ELISA（ELISA）Visible peristalsis visible intestinal peristalsis fatty acid binding protein in serum is determined respectively（I-FABP）, tumor necrosis factor
Son（TNF-α）, interleukin-6（IL-6）Content, ELISA kit be purchased from Shanghai Lang Dun companies, as a result see Fig. 2,** vs.
Sham p<0.01,## vs. I/R p<0.01, n=6.
Test result indicate that, small intestine cells are damaged and scorching caused by LNA-miR-665-3p can significantly mitigate ischemia-reperfusion
The release of sex factor.
The change of 1.3 small intestine's LC3 protein expressions
Using Western Blot methods determine small intestine in LC3 albumen expression, as a result as shown in figure 3,** vs.
Sham p<0.01,## vs. I/R p<0.01, n=6.Compared with Normal group, the ratio of LC3-II/ β-actin in model group
Example is significantly lowered, and after giving LNA-miR-665-3p, the ratio significantly rises, and indicates the recovery of autophagy level.Experiment knot
Fruit shows that LNA-miR-665-3p can significantly raise small intestine's autophagy level.
The change of 1.4 small intestine's Apoptosis
Histiocytic early apoptosis situation is detected using TUNEL methods, Fig. 4 is as a result seen.Model group is compared with Normal group TUNEL sun
Property cell number significantly increases, the visible green florescent signal for significantly increasing of the top of villi of fracture；Model administration group is compared with model group
TUNEL positive cell numbers are substantially reduced, and only see a small amount of green florescent signal in top of villi.Test result indicate that LNA-miR-
665-3p can significantly inhibit the Level of Apoptosis of small intestine.
The LNA-miR-665-3p of experimental example 2. significantly improves the survival rate of mouse II/R damages
The C57BL/6J mouse of 30 health are divided into 2 groups：
A. miRNA control groups：II/R+LNA-NC（2 mg/kg）；
B. LNA-miR-665-3p administration groups：II/R+LNA-miR-665-3p（2 mg/kg）；
As described in example 1, result is shown in Fig. 5 after the h of Reperfu- sion 24 for model construction and medication,* Vs. miRNA control groupsp<
0.01, n=15.Test result indicate that 24 hours survival rates of miR-665-3p administration groups animal are significantly higher than miRNA control groups.
Experimental example 3.Antagomir-miR-665-3p significantly mitigates the cellular damage of hypoxia-reoxygenation induction
Hypoxia-reoxygenation（Hypoxia/Reoxygenation, H/R）It is external conventional cellular damage model, for I/R in analogue body
Damage.Using Caco-2 cell construction H/R damage models, it is divided into 4 groups：
A. Normal group：Control+Antagomir-NC（30nM）；
B. model control group：H/R+Antagomir-NC（30nM）；
C. normal administration group：Control+Antagomir-665-3p（30nM）；
D. model administration group：H/R+Antagomir-665-3p（30nM）.
3.1 Antagomir-miR-665-3p significantly improve the survival rate after Caco-2 cells H/R is damaged
This experiment builds model using anoxic 12h reoxygenations 6h, after model construction success, is deposited using CCK-8 methods detection each group cell
Motility rate, is as a result shown in Fig. 6,** Vs. Control groupsp<0.01,## vs. H/R p<0.01, n=6.Test result indicate that, miR-
665-3p mortifiers are remarkably improved the tolerance that cell is damaged to H/R.
3.2 Antagomir-miR-665-3p significantly raise the autophagy flow horizontal after Caco-2 cells H/R is damaged
Using the autophagy flow horizontals in the double mark adenovirus methods detection cells of mRFP-GFP-LC3 autophagy, as a result as shown in fig. 7, with just
Normal control group is compared, and the number of autophagosome and autophagy lysosome is significantly lowered in H/R groups, and gives Antagomir-miR-
After 665-3p, the number significantly rises, and indicates the activation of autophagy stream.Test result indicate that, miR-665-3p mortifiers can
Autophagy flow horizontal significantly after activation Caco-2 cells H/R damages.
3.3 Antagomir-miR-665-3p significantly mitigate the Apoptosis after Caco-2 cells H/R is damaged
Using the Level of Apoptosis in TUNEL methods detection cell, as a result as shown in figure 8, compared with Normal group, H/R groups
Middle TUNEL positive cell numbers significantly rise, and after giving Antagomir-miR-665-3p, the number is significantly lowered, mark
The reduction of Apoptosis.Test result indicate that, after miR-665-3p mortifiers can significantly inhibit Caco-2 cells H/R damages
Level of Apoptosis.
3.4 Antagomir-miR-665-3p significantly mitigate the inflammatory factor release after Caco-2 cells H/R is damaged
Using ELISA（ELISA）TNF in cell supernatant is determined respectively（TNF-α）, interleukin-6
（IL-6）Content, ELISA kit be purchased from Shanghai Lang Dun companies, as a result see Fig. 9.Test result indicate that, miR-665-3p suppressions
Thing processed can significantly mitigate inflammatory factor release caused by H/R.
Sequence table
<110>Subsidiary Second Hospital, Dalian Medical Univ.
<120>Application of the miR-665-3p mortifiers in preventing and treating ischemical reperfusion injury medicine is prepared
<130>
<160>4
<210>1
<211>16
<212>DNA
<213>Artificial sequence, LNA-665-3p
<400>1
GACCTCAGCCTCCTGG
<210>2
<211>15
<212>DNA
<213>Artificial sequence, LNA-NC
<400> 2
ACGTCTATACGCCCA 15
<210>3
<211>20
<212>DNA
<213>Artificial sequence, Antagomir-665-3p
<400> 3
AGGGGCCUCAGCCUCCUGGU 20
<210>4
<211>21
<212>DNA
<213>Artificial sequence, Antagomir-NC
<400> 4
CAGUACUUUUGUGUAGUACAA 21
Claims (3)
1. application of a kind of miR-665-3p mortifiers in preventing and treating ischemical reperfusion injury medicine is prepared.
2. application of the miR-665-3p mortifiers in preventing and treating ischemical reperfusion injury medicine is prepared according to claim 1,
It is characterized in that the application in preventing and treating Intestinal ischemia reperfusion injury medicine is prepared.
3. application of the miR-665-3p mortifiers in preventing and treating ischemical reperfusion injury medicine is prepared according to claim 2,
It is characterized in that the DNA sequence dna of the miR-665-3p mortifiers such as SEQ ID NO:1 or SEQ ID NO:Shown in 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611217632.9A CN106692175A (en) | 2016-12-26 | 2016-12-26 | Application of miR-665-3p inhibitor to preparation of medicine for preventing and treating ischemia-reperfusion injuries |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611217632.9A CN106692175A (en) | 2016-12-26 | 2016-12-26 | Application of miR-665-3p inhibitor to preparation of medicine for preventing and treating ischemia-reperfusion injuries |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106692175A true CN106692175A (en) | 2017-05-24 |
Family
ID=58903393
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611217632.9A Pending CN106692175A (en) | 2016-12-26 | 2016-12-26 | Application of miR-665-3p inhibitor to preparation of medicine for preventing and treating ischemia-reperfusion injuries |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106692175A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107252491A (en) * | 2017-06-09 | 2017-10-17 | 汪道文 | Medicine and its screening technique and preparation method for treating heart failure |
| CN109136224A (en) * | 2018-08-21 | 2019-01-04 | 上海交通大学医学院附属瑞金医院 | MiR-221/222 and its inhibitor are used to prepare the drug of regulation liver fat deposition, liver fibrosis and hepatocellular carcinoma |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102791859A (en) * | 2009-12-15 | 2012-11-21 | 得克萨斯系统大学董事会 | Micro-RNA regulation in ischemia and ischemia-reperfusion injury |
| CN104053775A (en) * | 2011-10-17 | 2014-09-17 | 医药匈牙利2000有限公司 | Compounds for treatment of ischemic injury |
| CN104540527A (en) * | 2012-06-21 | 2015-04-22 | 米拉根医疗股份有限公司 | Inhibitors of the MIR-15 family of micro-RNAs |
| CN104988216A (en) * | 2015-06-08 | 2015-10-21 | 汪道文 | Serum miRNA relevant to chronic heart failure and application of serum miRNA |
-
2016
- 2016-12-26 CN CN201611217632.9A patent/CN106692175A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102791859A (en) * | 2009-12-15 | 2012-11-21 | 得克萨斯系统大学董事会 | Micro-RNA regulation in ischemia and ischemia-reperfusion injury |
| CN104053775A (en) * | 2011-10-17 | 2014-09-17 | 医药匈牙利2000有限公司 | Compounds for treatment of ischemic injury |
| CN104540527A (en) * | 2012-06-21 | 2015-04-22 | 米拉根医疗股份有限公司 | Inhibitors of the MIR-15 family of micro-RNAs |
| CN104988216A (en) * | 2015-06-08 | 2015-10-21 | 汪道文 | Serum miRNA relevant to chronic heart failure and application of serum miRNA |
Non-Patent Citations (1)
| Title |
|---|
| 王春阳等: "缺血后处理对大鼠肾脏miRNAs表达谱的影响", 《现代生物医学进展》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107252491A (en) * | 2017-06-09 | 2017-10-17 | 汪道文 | Medicine and its screening technique and preparation method for treating heart failure |
| CN107252491B (en) * | 2017-06-09 | 2021-06-29 | 汪道文 | Medicine for treating heart failure and screening method and preparation method thereof |
| CN109136224A (en) * | 2018-08-21 | 2019-01-04 | 上海交通大学医学院附属瑞金医院 | MiR-221/222 and its inhibitor are used to prepare the drug of regulation liver fat deposition, liver fibrosis and hepatocellular carcinoma |
| WO2020037797A1 (en) * | 2018-08-21 | 2020-02-27 | 上海市内分泌代谢病研究所 | Mir-221/222 and inhibitors thereof for use in preparing drugs and detection targets for regulating liver fat deposition, liver fibrosis and hepatocellular carcinoma |
| CN109136224B (en) * | 2018-08-21 | 2022-03-18 | 上海交通大学医学院附属瑞金医院 | miR-221/222 and inhibitor thereof for preparing medicine for regulating liver fat deposition, liver fibrosis and hepatocellular carcinoma |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110731955B (en) | Application of dimethyl itaconate in preventing and treating ulcerative colitis and canceration thereof | |
| Wu et al. | Pseudoephedrine/ephedrine shows potent anti-inflammatory activity against TNF-α-mediated acute liver failure induced by lipopolysaccharide/d-galactosamine | |
| CN107075515A (en) | C/EBP α compositions and application method | |
| WO2019107530A1 (en) | Therapeutic agent for inflammatory bowel disease | |
| Hagenlocher et al. | Cinnamon extract reduces symptoms, inflammatory mediators and mast cell markers in murine IL-10−/− colitis | |
| CN111743885B (en) | Application of p-hydroxyphenylacetic acid in preventing and/or treating cardiovascular diseases | |
| CN109963574B (en) | Composition for preventing or treating liver fibrosis comprising adipose stem cell-derived exosomes as active ingredient | |
| WO2016127847A1 (en) | Application of chlorogenic acid in preparing medicines for treating melanoma and medicines for treating melanoma | |
| CN106692175A (en) | Application of miR-665-3p inhibitor to preparation of medicine for preventing and treating ischemia-reperfusion injuries | |
| Lu et al. | Neuroprotection of Sanhua decoction against focal cerebral ischemia/reperfusion injury in rats through a mechanism targeting aquaporin 4 | |
| CN110903348A (en) | Small peptide for promoting wound healing and application thereof | |
| EP2191837A1 (en) | Blood sugar-modulating polypeptides | |
| TWI496579B (en) | Uses of zinc finger-like peptide, expression plasmid thereof, and pharmaceutical compositions containing the same | |
| CN102921021B (en) | MiRNA-361 (micro-ribonucleic acid-361) and application of antisense nucleotide thereof | |
| Fazili et al. | Royal jelly decreases MMP-9 expression and induces apoptosis in human bladder cancer 5637 cells | |
| KR102057226B1 (en) | Functional food composition for enhancing myofunction and athletic function comprising lotus leaf extract and manufacturing method thereof | |
| CN105596458A (en) | Jinqi glucose-lowering tablet for treating diabetic cardiovascular complications | |
| WO2021208551A1 (en) | Application of thyroid hormone and analogue thereof in preparation of drug for treating sickle-cell disease | |
| CN103316035A (en) | Use of sodium bicarbonate in preparation of medicines for treating cancer | |
| CN105085647B (en) | Natural anti-infective anti-oxidant bifunctional peptide Pb-CATH2 and its gene and application | |
| CN110484537A (en) | A kind of preparation method and application of miR-92 promotor and its injection | |
| CN114209728B (en) | Wild chrysanthemum active site with function of regulating epigenetic expression balance and resisting liver cancer as well as preparation method and application thereof | |
| KR101783444B1 (en) | Prevention or Treatment for ischemic stroke using miR-33-5p | |
| US20150196602A1 (en) | Stem cell therapy for crohn's disease and ulcerative colitis | |
| CN102888403A (en) | Application of micro ribonucleic acid (miRNA)-539 and miRNA-539antisense nucleotide, and medicinal composition for miRNA-539 antisense nucleotide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170524 |
|
| WD01 | Invention patent application deemed withdrawn after publication |